Monoamine oxidases are membrane-bounded flavo-enzymes, which catalyze the oxidative deamination of biogenic amines. Because of their important role in neurotransmitters inactivation, the dysfunction of MAO enzymes (increased levels of MAO activity) is associated with a number of mental and neurological disorders such as depression, anxiety disorders and migraine.
MAO enzymes exist in two isoforms, MAO-A and MAO-B, which have approximately 70% amino acid sequence identity (Oesch and Arand, Toxicology, Academic Press, San Diego USA, 1999) but differ in substrate specificity and tissue distribution (Bach et al., Proc. Natl. Acad. Sci. USA 85, 4934-4938, 1988). MAO-B enzyme is found in high level in the liver, platelets, and especially in brain (Cesura and Pletscher, Prog. Drug Res. 38, 171-297, 1992). The level of MAO-B activity in the brain increases with the age (Fowler et al., J. Neural Transm. 49, 1-20, 1980; Nictora et al., Neurtotoxicology 25, 155-165, 2004; Nagatsu, Neurotoxicology 25, 11-20, 2004.
Natural substrate for MAO-A is serotonin (5-HT) while MAO-B enzyme is elective for 2-phenylethylamine and benzylamine. Dopamine (DA), noradrenaline, adrenaline, tryptamine, and p-tyramine are substrates for both isoformes (Perez et al. Br. J. Pharmacol. 127, 869-876, 1999; Youdim et al. Nat. Rev. Neurosci. 7, 295-309, 2006). Another important substrate for MAO-B is the Parkinsonism-causing tertiary amine, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which is metabolized to the active neurotoxin, 1-methyl-4-phenylpyridinium cation (MPP+) in the brain by MAO-B (Youdim et al., Biochem. Pharmacol. 41, 155-162, 1991; Petzer et al., Bioorg. Med. Chem. 11, 1299-1310, 2003). This finding indicates a causal connection between MAO-B enzymatic activity and Parkinson's disease (Nagatsu, Neurotoxicology 25, 11-20, 2004). The process of oxidative deamination of cateholamines, such as dopamine, norepinephrine, and epinephrine, is essential for the correct function of synaptic neurotransmission in the brain (Bortolato et al., Adv. Drug Deliv. Rev. 60, 1527-1533, 2008). Furthermore, there are also studies providing the relationship between greater activity of MAO-B and increased cognitive damage of Alzheimer's disease patients (Benedetti and Dostert, Biochem. Pharmacol. 38, 555-561, 1989; Emilsson et al., Neuroscience Lett. 326, 56-60, 2002). The relationship between oxidative stress and the progressive neuronal impairment indicates that inhibition of MAO-B enzyme activity will have neuroprotective effect, probably by preventing the metabolism of monoamines such as dopamine and other neurotransmitters in the brain.
It is known, that MAO inhibitors (MAOI) are substances that inhibit the MAO activity and due to their selectivity of the MAO enzymes, they can be selective or non-selective. MAO-A inhibitors are therapeutically useful as antidepressants, whereas MAO-B inhibitors can be used in the monotherapy or in combination with levodopa (L-DOPA) for the treatment of Alzheimer's Disease, Parkinson's Disease and other neurological diseases associated with the degeneration of dopaminergic neurons in substantia nigra (Pålhagen et al., Neurology, 66, 1200-1206, 2006).
The current therapy of AD and PD is primarily focused on the treatment of the symptoms affecting patient's quality of live. Most of the currently approved medicines are based on dopamine replacement using dopamine-enhancing approach such as levodopa and dopamine agonists that stimulate dopamine production. MAO-B inhibitors are also used as an alternative therapeutic approach for the treatment of neurodegenerative diseases. For example, the irreversible MAO-B inhibitors selegiline (Movergan, Deprenyl, Antiparkin, Xilopar; Riederer and Lachenmayer, J. Neural Transm., 110 (11), 1273-8, 2003) and rasagiline (Azilect; Lakhan, Molecular Neurodegeneration, 2(13), 2007) are used as monotherapeutics in early PD and anjuctive therapy to levodopa in late-stage PD. The therapeutic effect of MAO-B inhibitors is associated with the blockage of the oxidative activity of the monoamine oxidase B (MAO-B) enzyme in the brain.
Patent application WO2005/004801 discloses a number of indole, azaindole and related N-substituted piperazine derivatives, wherein the 1H-pyrrolo[2,3-c]pyridine and 1H-pyrrolo[3,2-b]pyridine moieties are attached to the general piperazine unit via an oxalyl spacer. The 1H-pyrrolo[2,3-c]pyridine and 1H-pyrrolo[3,2-b]pyridine moieties do not contain a disubstituted benzamide residue. These compounds are described as antivirals, anti-inflammatory and immunomodulatory activity and are useful in the treatment of HIV/AIDS.
Patent EP0842934 discloses pyrrolo[3,2-b]pyridine derivatives bearing two substituents in the positions 3 and 7. The compounds are potentially useful as 5-HT1F agonists for the treatment of migraine.
Patent EP1784404 describes new pirrolo[2,3-c]pyridine derivatives, including as a substituent in the pirrole ring a substituted benzamide and simultaneously a 1,2,3,4-tetrahydroisoguinile group, or substituted such group and substituents at second and third position in the pirrole ring. These substances are used as proton pump inhibitors.
It is therefore an object of the present invention to provide substituted benzamide derivatives, their salts, isomers or mixtures of them, applicable as in vitro selective MAO-B inhibitors for the prevention and treatment of acute and chronic neurological disorders, cognitive and neurodegenerative diseases.